{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T15:26:41Z","timestamp":1785252401765,"version":"3.55.0"},"reference-count":51,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,12,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hemophagocytic lymphohistiocytosis (HLH) and the related HLH-spectrum disorders macrophage activation syndrome, macrophage activation-like syndrome, and treatment-associated immune-effector-cell\u2013associated HLH-like syndrome are extreme forms of too much inflammation (TMI). Adult patients with HLH associated with hematologic malignancies have a 70% to 80% mortality rate due to delayed diagnosis, prolonged immunosuppression with associated secondary infections, and disease recurrence. In recent years, educational efforts and epidemiological evolution have increased diagnostic awareness. This has been catalyzed by the COVID-19 pandemic, the first approved anti-interferon gamma antibody for primary relapsed\/refractory HLH, advancements in the treatment of posttransplant graft-versus-host disease, and the broad availability of T-cell\u2013engaging therapeutics. These truly challenging-to-diagnose entities under the cytokine storm umbrella confer TMI, causing multiorgan dysfunction and early death. Novel prognostic models, differential diagnosis with the help of advanced diagnostic algorithms, preemptive therapeutic interventions, and more individualized cytokine-directed treatment options have moved this previously neglected area in adult hematology to the forefront of the hematologist's daily practice.<\/jats:p>","DOI":"10.1182\/hematology.2025000707","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T14:08:00Z","timestamp":1764943680000},"page":"206-214","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":2,"title":["Hemophagocytic lymphohistiocytosis: do we have a solution for TMI (too much inflammation)?"],"prefix":"10.1182","volume":"2025","author":[{"given":"Paul","family":"La Ros\u00e9e","sequence":"first","affiliation":[{"name":"1 Schwarzwald-Baar-Klinikum, Klinik f\u00fcr Innere Medizin II, Onkologie, H\u00e4matologie, Immunologie, Infektiologie u. Palliativmedizin, Villingen-Schwenningen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafal","family":"Machowicz","sequence":"additional","affiliation":[{"name":"2 Medical University of Warsaw, Department of Hematology, Transplantation and Internal Medicine, Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2025,12,5]]},"reference":[{"issue":"11","key":"2025120616324357800_hem2025000707C1","doi-asserted-by":"crossref","first-page":"e797","DOI":"10.1097\/HS9.0000000000000797","article-title":"Temporal trends in the incidence of hemophagocytic lymphohistiocytosis: a nationwide cohort study from England 2003-2018","volume":"6","author":"West","year":"2022","journal-title":"Hemasphere"},{"issue":"3","key":"2025120616324357800_hem2025000707C2","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1182\/blood.2023020715","article-title":"Malignancy-associated hemophagocytic lymphohistiocytosis in Sweden: incidence, clinical characteristics, and survival","volume":"143","author":"L\u00f6fstedt","year":"2024","journal-title":"Blood"},{"issue":"7","key":"2025120616324357800_hem2025000707C3","doi-asserted-by":"crossref","first-page":"438.e1","DOI":"10.1016\/j.jtct.2023.03.006","article-title":"Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome","volume":"29","author":"Hines","year":"2023","journal-title":"Transplant Cell Ther"},{"issue":"6","key":"2025120616324357800_hem2025000707C4","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1056\/NEJMra2314005","article-title":"Hemophagocytic lymphohistiocytosis","volume":"392","author":"Henter","year":"2025","journal-title":"N Engl J Med"},{"key":"2025120616324357800_hem2025000707C5","doi-asserted-by":"crossref","first-page":"102143","DOI":"10.1016\/j.eclinm.2023.102143","article-title":"Epidemiology, characteristics, and outcomes of adult haemophagocytic lymphohistiocytosis in the USA, 2006-19: a national, retrospective cohort study","volume":"62","author":"Abdelhay","year":"2023","journal-title":"EClinicalMedicine"},{"issue":"10","key":"2025120616324357800_hem2025000707C6","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1182\/blood.2023022281","article-title":"Survival in primary hemophagocytic lymphohistiocytosis, 2016 to 2021: etoposide is better than its reputation","volume":"143","author":"B\u00f6hm","year":"2024","journal-title":"Blood"},{"key":"2025120616324357800_hem2025000707C7","article-title":"Familial hemophagocytic lymphohistiocytosis","volume-title":"GeneReviews","author":"Zhang","year":"2006"},{"issue":"1","key":"2025120616324357800_hem2025000707C8","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1182\/hematology.2023000463","article-title":"Inflamed-HLH, MAS, or something else?","volume":"2023","author":"Kumar","year":"2023","journal-title":"Hematology Am Soc Hematol Educ Program"},{"issue":"23","key":"2025120616324357800_hem2025000707C9","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.1182\/blood.2018894618","article-title":"Recommendations for the management of hemophagocytic lymphohistiocytosis in adults","volume":"133","author":"La Ros\u00e9e","year":"2019","journal-title":"Blood"},{"issue":"5","key":"2025120616324357800_hem2025000707C10","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1016\/j.jaip.2018.05.031","article-title":"Recommendations for the use of etoposide-based therapy and bone marrow transplantation for the treatment of HLH: consensus statements by the HLH steering committee of the histiocyte society","volume":"6","author":"Ehl","year":"2018","journal-title":"J Allergy Clin Immunol Pract"},{"issue":"1","key":"2025120616324357800_hem2025000707C11","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.jaci.2023.07.023","article-title":"Severe adult hemophagocytic lymphohistiocytosis (HLHa) correlates with HLH-related gene variants","volume":"153","author":"Bloch","year":"2024","journal-title":"J Allergy Clin Immunol"},{"issue":"22","key":"2025120616324357800_hem2025000707C12","doi-asserted-by":"crossref","first-page":"2308","DOI":"10.1182\/blood.2024025077","article-title":"Diagnostic guidelines for familial hemophagocytic lymphohistiocytosis revisited","volume":"144","author":"Henter","year":"2024","journal-title":"Blood"},{"issue":"9","key":"2025120616324357800_hem2025000707C13","doi-asserted-by":"crossref","first-page":"2613","DOI":"10.1002\/art.38690","article-title":"Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome","volume":"66","author":"Fardet","year":"2014","journal-title":"Arthritis Rheumatol"},{"issue":"5","key":"2025120616324357800_hem2025000707C14","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1007\/s00277-013-1925-8","article-title":"A high sIL-2R\/ferritin ratio is a useful marker for the diagnosis of lymphoma-associated hemophagocytic syndrome","volume":"93","author":"Tsuji","year":"2014","journal-title":"Ann Hematol"},{"issue":"7","key":"2025120616324357800_hem2025000707C15","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1182\/blood.2021012764","article-title":"An improved index for diagnosis and mortality prediction in malignancy-associated hemophagocytic lymphohistiocytosis","volume":"139","author":"Zoref-Lorenz","year":"2022","journal-title":"Blood"},{"issue":"2","key":"2025120616324357800_hem2025000707C16","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/s41375-024-02135-8","article-title":"Lymphoma-associated hemophagocytic lymphohistiocytosis (LA-HLH): a scoping review unveils clinical and diagnostic patterns of a lymphoma subgroup with poor prognosis","volume":"38","author":"Knauft","year":"2024","journal-title":"Leukemia"},{"issue":"26","key":"2025120616324357800_hem2025000707C17","doi-asserted-by":"crossref","first-page":"e26509","DOI":"10.1097\/MD.0000000000026509","article-title":"Systems controls are needed to reduce mistaken tests for hemophagocytic lymphohistiocytosis, results of a prospective quality-improvement cohort study","volume":"100","author":"Safi","year":"2021","journal-title":"Medicine (Baltimore)"},{"issue":"4","key":"2025120616324357800_hem2025000707C18","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/s00277-010-1101-3","article-title":"Random skin biopsy and bone marrow biopsy for diagnosis of intravascular large B cell lymphoma","volume":"90","author":"Matsue","year":"2011","journal-title":"Ann Hematol"},{"issue":"1","key":"2025120616324357800_hem2025000707C19","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1002\/hon.2819","article-title":"Diagnostic strategy for trigger identification in severe reactive hemophagocytic lymphohistiocytosis: a diagnostic accuracy study","volume":"39","author":"Tudesq","year":"2021","journal-title":"Hematol Oncol"},{"issue":"2","key":"2025120616324357800_hem2025000707C20","first-page":"e1046","article-title":"Ruxolitinib, IV immunoglobulin, and high-dose glucocorticoids for critically ill adults with secondary hemophagocytic lymphohistiocytosis: a single-center observational pilot study","volume":"6","author":"Scholz","year":"2024","journal-title":"Crit Care Explor"},{"issue":"3","key":"2025120616324357800_hem2025000707C21","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1182\/blood.2024026139","article-title":"Ruxolitinib combined with dexamethasone for adult patients with newly diagnosed hemophagocytic lymphohistiocytosis in China","volume":"146","author":"Zhou","year":"2025","journal-title":"Blood"},{"issue":"1","key":"2025120616324357800_hem2025000707C22","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/s41408-024-01056-0","article-title":"Combined emapalumab and ruxolitinib in patients with haemophagocytic lymphohistiocytosis","volume":"14","author":"Song","year":"2024","journal-title":"Blood Cancer J"},{"issue":"4","key":"2025120616324357800_hem2025000707C23","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1177\/1078155219878774","article-title":"Ruxolitinib for the treatment of lymphoma-associated hemophagocytic lymphohistiocytosis: a cautionary tale","volume":"26","author":"Trantham","year":"2020","journal-title":"J Oncol Pharm Pract"},{"issue":"5","key":"2025120616324357800_hem2025000707C24","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1097\/CCM.0000000000005361","article-title":"Consensus-based guidelines for the recognition, diagnosis, and management of hemophagocytic lymphohistiocytosis in critically ill children and adults","volume":"50","author":"Hines","year":"2022","journal-title":"Crit Care Med"},{"issue":"17","key":"2025120616324357800_hem2025000707C25","doi-asserted-by":"crossref","first-page":"4515","DOI":"10.1182\/bloodadvances.2024014005","article-title":"The OHI index predicts early mortality from organ dysfunction and survival benefit from etoposide in patients with lymphoma","volume":"9","author":"Zoref-Lorenz","year":"2025","journal-title":"Blood Adv"},{"key":"2025120616324357800_hem2025000707C26","doi-asserted-by":"crossref","first-page":"9636897211057077","DOI":"10.1177\/09636897211057077","article-title":"Autologous hematopoietic stem cell transplantation for patients with lymphoma-associated hemophagocytic lymphohistiocytosis","volume":"30","author":"Song","year":"2021","journal-title":"Cell Transplant"},{"issue":"3","key":"2025120616324357800_hem2025000707C27","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.annonc.2021.12.002","article-title":"The ECHELON-2 trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma","volume":"33","author":"Horwitz","year":"2022","journal-title":"Ann Oncol"},{"issue":"1","key":"2025120616324357800_hem2025000707C28","doi-asserted-by":"crossref","first-page":"84","DOI":"10.4049\/jimmunol.1302282","article-title":"Etoposide selectively ablates activated T cells to control the immunoregulatory disorder hemophagocytic lymphohistiocytosis","volume":"192","author":"Johnson","year":"2014","journal-title":"J Immunol"},{"issue":"11","key":"2025120616324357800_hem2025000707C29","doi-asserted-by":"crossref","first-page":"2989","DOI":"10.1007\/s00277-023-05271-w","article-title":"Delay in treatment of adult hemophagocytic lymphohistiocytosis is associated with worse in-hospital outcomes","volume":"102","author":"Abdelhay","year":"2023","journal-title":"Ann Hematol"},{"issue":"1","key":"2025120616324357800_hem2025000707C30","doi-asserted-by":"crossref","first-page":"e29","DOI":"10.3324\/haematol.2019.220301","article-title":"Dose-adjusted EPOCH regimen as first-line treatment for non-Hodgkin lymphoma-associated hemophagocytic lymphohistiocytosis: a single-arm, open-label, phase II trial","volume":"105","author":"Liang","year":"2020","journal-title":"Haematologica"},{"issue":"1","key":"2025120616324357800_hem2025000707C31","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s40164-022-00362-2","article-title":"The role of etoposide in the treatment of adult patients with hemophagocytic lymphohistiocytosis","volume":"12","author":"Zondag","year":"2023","journal-title":"Exp Hematol Oncol"},{"key":"2025120616324357800_hem2025000707C32","doi-asserted-by":"crossref","first-page":"107606","DOI":"10.1016\/j.intimp.2021.107606","article-title":"Rituximab-containing immuno-chemotherapy regimens are effective for the elimination of EBV for EBV-HLH with only and mainly B lymphocytes of EBV infection","volume":"96","author":"Meng","year":"2021","journal-title":"Int Immunopharmacol"},{"issue":"12","key":"2025120616324357800_hem2025000707C33","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1182\/bloodadvances.2017005561","article-title":"Proliferation through activation: hemophagocytic lymphohistiocytosis in hematologic malignancy","volume":"1","author":"Vick","year":"2017","journal-title":"Blood Adv"},{"issue":"3","key":"2025120616324357800_hem2025000707C34","doi-asserted-by":"crossref","first-page":"474","DOI":"10.3324\/haematol.2013.097394","article-title":"Hemophagocytic syndrome in patients with acute myeloid leukemia undergoing intensive chemotherapy","volume":"99","author":"Delavigne","year":"2014","journal-title":"Haematologica"},{"issue":"7","key":"2025120616324357800_hem2025000707C35","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/S2213-2600(25)00124-9","article-title":"Sepsis in patients who are immunocompromised: diagnostic challenges and future therapies","volume":"13","author":"Deinhardt-Emmer","year":"2025","journal-title":"Lancet Respir Med"},{"issue":"11","key":"2025120616324357800_hem2025000707C36","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1007\/s00277-011-1170-y","article-title":"Drug-induced lymphadenopathy with eosinophilia and renal failure mimicking lymphoma disease: dramatic onset of DRESS syndrome associated with antibiotic treatment","volume":"90","author":"Schnetzke","year":"2011","journal-title":"Ann Hematol"},{"issue":"2","key":"2025120616324357800_hem2025000707C37","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1097\/CCM.0000000000001402","article-title":"Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial","volume":"44","author":"Shakoory","year":"2016","journal-title":"Crit Care Med"},{"issue":"4","key":"2025120616324357800_hem2025000707C38","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1097\/CCM.0000000000004131","article-title":"Hyperferritinemia in critically ill patients","volume":"48","author":"Lachmann","year":"2020","journal-title":"Crit Care Med"},{"issue":"1","key":"2025120616324357800_hem2025000707C39","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1186\/s12916-017-0930-5","article-title":"Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis","volume":"15","author":"Kyriazopoulou","year":"2017","journal-title":"BMC Med"},{"issue":"5","key":"2025120616324357800_hem2025000707C40","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1182\/blood.2019003664","article-title":"Functional and genetic testing in adults with HLH reveals an inflammatory profile rather than a cytotoxicity defect","volume":"136","author":"Carvelli","year":"2020","journal-title":"Blood"},{"issue":"25","key":"2025120616324357800_hem2025000707C41","doi-asserted-by":"crossref","first-page":"2992","DOI":"10.1182\/blood.2024027954","article-title":"Beyond genotype: challenges in predicting disease risk for carriers of biallelic perforin variants","volume":"145","author":"Wegehaupt","year":"2025","journal-title":"Blood"},{"issue":"1","key":"2025120616324357800_hem2025000707C42","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41392-025-02178-y","article-title":"Deep insight into cytokine storm: from pathogenesis to treatment","volume":"10","author":"Nie","year":"2025","journal-title":"Signal Transduct Target Ther"},{"issue":"9","key":"2025120616324357800_hem2025000707C43","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.1038\/s41591-024-03084-6","article-title":"A systematic review and meta-analysis of nonrelapse mortality after CAR T cell therapy","volume":"30","author":"Cordas","year":"2024","journal-title":"Nat Med"},{"issue":"26","key":"2025120616324357800_hem2025000707C44","doi-asserted-by":"crossref","first-page":"5154","DOI":"10.1182\/blood-2013-02-485623","article-title":"Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy","volume":"121","author":"Teachey","year":"2013","journal-title":"Blood"},{"issue":"2","key":"2025120616324357800_hem2025000707C45","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1002\/art.42985","article-title":"Emapalumab treatment in patients with rheumatologic disease-associated hemophagocytic lymphohistiocytosis in the United States: a retrospective medical chart review study","volume":"77","author":"Chandrakasan","year":"2025","journal-title":"Arthritis Rheumatol"},{"issue":"6","key":"2025120616324357800_hem2025000707C46","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1136\/annrheumdis-2017-212608","article-title":"Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still's disease","volume":"77","author":"Gabay","year":"2018","journal-title":"Ann Rheum Dis"},{"issue":"1","key":"2025120616324357800_hem2025000707C47","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1182\/blood-2024-204230","article-title":"ELA026, a monoclonal antibody targeting signal regulatory protein-\u03b1\/\u03b21\/\u03b3, rapidly controls inflammation and improves 2-month survival in treatment-na\u00efve malignancy-associated hemophagocytic lymphohistiocytosis","volume":"144","author":"Maiti","year":"2024","journal-title":"Blood"},{"issue":"1","key":"2025120616324357800_hem2025000707C48","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1186\/s13023-025-03698-0","article-title":"Perspectives on the current diagnostic and treatment paradigms in secondary hemophagocytic lymphohistiocytosis (HLH)","volume":"20","author":"Naymagon","year":"2025","journal-title":"Orphanet J Rare Dis"},{"issue":"1","key":"2025120616324357800_hem2025000707C49","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nrclinonc.2017.148","article-title":"Chimeric antigen receptor T-cell therapy\u2014assessment and management of toxicities","volume":"15","author":"Neelapu","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"issue":"3","key":"2025120616324357800_hem2025000707C50","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1002\/art.39332","article-title":"2016 classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: A European League Against Rheumatism\/American College of Rheumatology\/Paediatric Rheumatology International Trials Organisation collaborative initiative","volume":"68","author":"Ravelli","year":"2016","journal-title":"Arthritis Rheumatol"},{"issue":"7","key":"2025120616324357800_hem2025000707C51","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1038\/s41375-020-0891-0","article-title":"The janus kinase 1\/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation","volume":"34","author":"La Ros\u00e9e","year":"2020","journal-title":"Leukemia"}],"container-title":["Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/hematology\/article-pdf\/2025\/1\/206\/2469926\/206larosee.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/hematology\/article-pdf\/2025\/1\/206\/2469926\/206larosee.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T21:32:53Z","timestamp":1765056773000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/hematology\/article\/2025\/1\/206\/556884\/Hemophagocytic-lymphohistiocytosis-do-we-have-a"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,5]]},"references-count":51,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12,5]]},"published-print":{"date-parts":[[2025,12,5]]}},"URL":"https:\/\/doi.org\/10.1182\/hematology.2025000707","relation":{},"ISSN":["1520-4391","1520-4383"],"issn-type":[{"value":"1520-4391","type":"print"},{"value":"1520-4383","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,12,5]]},"published":{"date-parts":[[2025,12,5]]}}}